Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin.

Noriyasu Kamei,Natsuki Yokoyama,Maika Yamaguchi,Yukio Ago,Hidemi Bando,Mariko Takeda-Morishita,Ayaka Hashimoto,Takanori Kanazawa,Susumu Suwabe,Erina Tanaka,Kenji Arime,Kaho Murata

doi:10.3390/pharmaceutics13111745

Noriyasu Kamei, Natsuki Yokoyama + Show 10 more

Open Access

https://doi.org/10.3390/pharmaceutics13111745

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Abstract

We previously found that coadministering peptides and proteins with the cell-penetrating peptide L-penetratin intranasally significantly increased transport to the brain and enhanced pharmacological effects. The present study aimed to clarify the mechanisms of nose-to-brain drug delivery enhancement by L-penetratin coadministration. First, we compared the concentrations of Exendin-4 in plasma and brain after intranasal and subcutaneous administration and suggested that coadministration with L-penetratin facilitated the direct nose-to-brain transport of Exendin-4. Second, we demonstrated that L-penetratin did not stimulate the transport of Cy7-labeled Exendin-4 and insulin through the trigeminal nerves but shifted their distribution to the olfactory mucosal pathway. Third, we investigated the distribution of insulin into the deeper regions of the brain after delivery via the olfactory pathway and suggested that insulin had entered the olfactory bulb, bottom part of the brain, and perivascular space through the cerebrospinal fluid and had diffused throughout the brain. We further demonstrated that intranasally delivered insulin with L-penetratin specifically accumulated on the hippocampus neuronal cells. Thus, this study suggested that administrating peptide drugs intranasally with L-penetratin allows direct transport to the olfactory bulb, bottom part of the brain, and perivascular space of the cerebral artery. This technique also potentially allows targeting of specific brain areas.

Highlights

IntroductionThe brain is a sanctuary protected from the external environment by the blood–brain barrier (BBB), composed of microvascular endothelial cells, astrocytes, pericytes, and others, which drastically limits the influx of drugs from systemic circulation to the brain parenchyma [1]
We previously demonstrated that intranasal coadministration with L-penetratin, a typical amphipathic cell-penetrating peptide (CPP), significantly increased the delivery of insulin, Exendin-4, and leptin to the brain [9,12,14,15]
During the permeation through the nasal mucosa, drugs come across microvascular vessels in the lamina propria directed toward the systemic circulation before reaching the brain or cerebrospinal fluid (CSF) [3]

Summary

Introduction

The brain is a sanctuary protected from the external environment by the blood–brain barrier (BBB), composed of microvascular endothelial cells, astrocytes, pericytes, and others, which drastically limits the influx of drugs from systemic circulation to the brain parenchyma [1]. Most therapeutic drugs cannot be delivered to the brain via peripheral administration routes such as intravenous and subcutaneous (s.c.) injections [2]. Neurotrophic proteins and nucleic acids such as mRNA and siRNA could potentially treat neurodegenerative disorders, cerebral ischemic injuries, and brain tumors. Their bulky structures and high sensitivity to enzymatic degradation prevent them from

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